CN1317979A - 用于治疗青光眼的5-羟色胺激活性激动剂 - Google Patents
用于治疗青光眼的5-羟色胺激活性激动剂 Download PDFInfo
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Abstract
本发明公开了可有效治疗青光眼,包括降低眼压的具有5HT2受体激动剂活性的化合物。本发明还公开了组合物及它们的使用方法。
Description
本发明涉及具有5-羟色胺激活性5HT2激动剂活性(化合物)的化合物在治疗青光眼,包括降低眼压方面的应用。
发明背景
5-羟色胺(5HT)是一种内源性生物胺,已证实在机体的许多组织包括眼睛中具有神经递质功能[Zifa和Fillion,药理学综述(Pharmacol.Rev.),44,401(1991);Hoyer等,药理学综述,46,157(1994);Tobin等神经科学杂志(J.Neurosci.),8,3713(1988)]。
5HT可以与至少7种主要5HT受体(5HT1-5HT7)及这些家族中的其它亚型反应,以启动细胞内生化事件如刺激第二信使(如cAMP,肌醇三磷酸),逐步导致最终生物应答,例如,组织收缩或激素释放等[Hoyer等,出处同上;Martin等,Trends Pharmacol.Sci.,19,2(1998)]。当被5HT激活时,5HT1家族内的受体亚型与腺苷酰环化酶(AC)阴性地偶联并抑制cAMP的产生,而5HT4、5HT6和5HT7受体都与AC阳性地偶联并因此刺激cAMP的产生[Martin等,出处同上]。5HT3不同于其它,它与一个离子通道相偶联,该通道可允许钠、钾和钙出入[Hoyer等,出处同上]。
当被5HT激活时,5HT2家族的受体与磷脂酶C(PLC)阳性地偶联,并因此产生磷脂酰肌醇和使胞内钙流动。5HT2受体分类包括5HT2A、5HT2B、和5HT2C受体亚型,所有亚型都有高度相似的氨基酸序列。在较早(约1990年之前)的命名原则中称作5HT1C的受体,被重新分类为5HT2C受体,因为根据分子克隆及其药理学特性,它与其它的5HT2家族PLC偶联受体更类似[Hoyer等,1994]。
5-羟色胺激活性神经支配眼睛[Tobin等,神经科学杂志,8,3713(1998)],在人眼部房水中发现了5HT[Martin等,眼科学(Ophthalmol),95,1221(1998)]。另外,[3H]5HT的受体结合位点已在兔子的虹膜睫状体(ICB)中证实并鉴定了药理学特征[Mallorga和Sugrus,Curr.Eye Res.,6,527(1987)以及Chidlow等,Invest.Ophthalmol.Vis.Sci.,36,2238(1995)]。在兔子中,这些5HT结合位点显示出功能地偶联到第二信使产物[Tobin和Osborne,神经化学杂志(J.Neurochem),53,686(1989)以及Tobin等,神经化学杂志,出处同上]。在人体ICB中,这些结合位点被描绘成5HT1A和5HT2受体[Barnet和Osborne,Exp.Eye Res.,57,209(1993)]。另外,已报道在兔子的ICB中出现了5HT1A和5HT7受体的mRNAs[Chidlow等,Invest.Ophthalmol.Vis.Sci.,出处同上以及Osborne和Chidlow,Ophthalmologica,210,308(1996)]。尚未知在眼睛中这些受体的准确功能。
局部用于兔眼部的5HT或5-氨甲酰色胺(carboxamidotryptamine)(5-CT)使眼压升高(IOP)[Meyer-Bothling等,Invest.Ophthalmol.Vis.Sci.,34,3035(1993)]。相反,另一组显示在兔子中局部应用5HT使眼压降低;然而,兔子眼房内施用5HT,使IOP升高并导致血-水屏障被打破[Krootila等,J.Ocular Pharmacol.,3,279(1987)]。此外,受试人口服5HT吸收抑制剂氟西汀(fluoxetine)(Prozac)也使IOP升高[Costagliola等,英国眼科学杂志(Br.J.Ophthalmol.),80,678(1996)]并可能导致青光眼[Ahmad,Ann.Pharmacother,25,436(1992)]。然而,与5HT、5-CT和氟西汀的IOP升高效应有关的5HT受体亚型目前未知。
用8-羟基DPAT和MKC-242(5HT1A激动剂)处理兔子的研究表明这些化合物降低IOP[Osborne和Chidlow,Ophthalmologica,210,308(1996)以及EP0771563-A2]。此外,在猴的青光眼5-甲基哌胺甲尿啶(methylurapidil)(5HT1A激动剂)降低IOP[Wang等,Curr.Eye Res.,16,679(1997)]。MKC-242和5-甲基哌胺甲尿啶是比较有效的α1受体拮抗剂(已知α1拮抗剂降低兔子、猴子和人类的IOP)。5-甲基哌胺甲尿啶降低IOP的作用机理在于其α1拮抗剂活性而非其5HT1A激动剂活性[Wang等,Invest.Ophthalmol.Vis.Sci.,39(增刊),2236(1998)]。美国专利5,693,654公开了用于降低IOP的5HT1样(现称为5HT1D)受体激动剂,如舒马曲坦(sumatriptan)。WO/9911619公开了有可能有效治疗青光眼的5HT2A拮抗剂。
二甲麦角新碱(methysergide)(5HT2拮抗剂,也具有其它活性)在兔子中降低IOP[Krootila等,Exp.Eye Res.,出处同上]。也具有显著的α1拮抗剂活性的酮舍林(ketanserin)(5HT2A/C拮抗剂)在兔子和人类中降低IOP[Chan等,眼科药理学杂志(J.Ocular Pharmacol.),1,137(1985)以及Costagliola等,Exp.Eye Res.,52,507(1991)]。saprogrelate(5HT2A拮抗剂)局部应用或口服应用于兔子和人时,降低IOP[Mano等,Invest.Ophthal.Vis.Sci.,36(增刊),3322(1995)以及Takenaka等,Invest.Ophthal.Vis.Sci.,36(增刊),3390(1995)]。EP522226和美国专利5,290,781公开了酮舍林及其衍生物在高眼压治疗中的应用。美国专利5,290,781和5,106,555公开了某种5HT2拮抗剂在降低IOP中的应用。美国专利5,652,272公开了saprogrelate在降低IOP中的应用。美国专利5,538,974公开了某种5HT2拮抗剂的眼药组合物在降低IOP中的应用。WO/9911619公开了有可能有效治疗青光眼的5HT2A拮抗剂。
美国专利5,011,846公开了某种用于治疗青光眼的5HT3受体拮抗剂。
WO97/17345公开了具有5HT4 5-羟色胺激活性受体激动剂或拮抗剂活性的特定化合物可有效治疗精神病、胃肠道疾病、泌尿外道(lower urinary)疾病和心血管疾病。此文提到这些化合物可能对青光眼有效。
由上述可见,尚不清楚哪一种5-羟色胺激活性受体活性导致IOP降低。此外,已知许多这类化合物对已知与降低IOP有关的非-5-羟色胺激活性受体具有活性。
发明简述
本发明涉及具有5HT2受体激动剂活性的化合物在青光眼治疗,包括降低眼压中的应用。本发明还涉及所述化合物的组合物的这类应用。
优选实施方案的详述
意外地发现对5HT2受体具有激动剂活性的5-羟色胺激活性化合物可有效降低和控制已升高的IOP,并可用于治疗青光眼。
本发明化合物的具体实例包括:1)(R)-4-碘-2,5-二甲氧基-α-甲基-苯乙酰胺[(R)-DOI],最主要的(prototypical)选择性5HT2激动剂,对5HT2受体亚型不具有选择性[Baxter等,Trends.Pharmacol.Sci.,16,105(1995)];2)α-甲基-5-羟色胺,对受体亚型具有适度选择性(5HT2B>5HT2C>5HT2A)的高效5HT2激动剂[Baxter等,出处同上];3)5-甲氧基-α-甲基色胺,与α-甲基-5-羟色胺的特征相似[Nichols等,医学化学杂志(J.Med.Chem.),31,1406(1998)]。下列参考文献并非限制,而是例举本发明可用的化合物,均引入本文以作参考:美国专利5,861,425;5,646,173;5,578,612;5,571,833;5,545,644;5,494,928;4,659,706和4,487,773;已公开的欧洲专利说明书863,136;已公开的国际专利申请WO98/56768;WO98/31354;WO98/30548;WO98/30546。此外在下列出版物中公开的化合物进一步作为根据本发明可用的化合物的例子,也收录在此作为参考:Parker等,医学化学杂志,41,5148(1998);Vangveravong等,医学化学杂志,41,4995(1998);Albertini等,诱变(Mutagenesis),13,397(1998);Monte等,医学化学杂志,40,2997(1997);Bs等,欧洲医学化学杂志,32,253(1997);Bs等,医学化学杂志,40,2762(1997);Monte等,医学化学杂志,39,2952(1996);Glennon等,医学化学杂志,37,1929(1994);Macor等,四面体通讯(Tetrahedron Lett.),35,45(1994);Macor等,医学化学杂志,35,4503(1992);Macor等,医学化学杂志,35,3625(1992);Glennon等,医学化学杂志,35,734(1992);Seggel等,医学化学杂志,33,1032(1990)。
现已认识到上述化合物中很多具有不对称原子,因而所有对映体和非对映体都考虑到了。还考虑到了化合物的可药用盐及自由基。将所述化合物施用于眼(例如,局部、眼房内、或经植入)。优选将所述化合物掺入局部用眼药制剂中以便运送至眼。化合物可以与眼科可接受的防腐剂、表面活性剂、增粘剂、增渗剂、缓冲液、氯化钠和水结合形成含水、无菌眼用悬浮液或溶液。眼用溶液可通过将化合物溶解在生理可接受的等渗缓冲液中而制备。而且,眼用溶液可包括一种眼科可接受的表面活性剂以帮助溶解所述化合物。此外,眼用溶液可包含一种增加粘度的试剂,例如:羟甲基纤维素,羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮等,以增加该眼用溶液在结膜囊中的滞留期。还可使用胶凝剂,包括但不限于吉兰糖胶(gellan)和黄原胶。为了制备无菌眼膏制剂,将活性成分与一种防腐剂在适当的赋形剂,如矿物油、液态羊毛脂或白凡士林中组合。无菌眼胶通过按已公开的类似眼用剂的配方将活性成分悬浮在一种亲水基质中而制备,并可加入防腐剂和张度剂,其中该亲水基质用如carbopol-940等组合而制备。
优选将所述化合物配制成眼部局部用悬浮液或溶液,pH约5-8。所述化合物在这些制剂中通常占重量的0.01%-5%,优选占重量的0.25%-2%。因此,根据有经验的临床医师的常规判断,局部用药可以是将1-2滴这类制剂施用于眼部表面,每天1-4次。
所述化合物也可组合用于治疗青光眼的其它药剂,例如但不限于,β-阻滞剂、前列腺素、碳酸酐酶抑制剂、α2激动剂和缩瞳剂。所述化合物也可与钙离子通道阻滞剂、易代谢性(metabotropic)及离子化谷氨酸受体的拮抗剂、和/或与它们相关的结合位点,如多胺和马钱子碱不敏感性甘氨酸位点的拮抗剂。这些药剂可以局部投药,但通常全身用药。
特别优选的组合物包括具有α2肾上腺素能试剂的化合物,如阿普尼啶(apraclonidine)或布莫尼啶(brimonidine)或其可药用盐。
本发明中有用的化合物可以用本领域技术人员熟知的方法鉴别。这种选择始于5HT2受体结合试验,下面描述了一个这样的实施例。本发明的化合物对5HT2受体具有高亲和力(IC50或Ki值约为20nM或更小,且该亲和力高于对其它5HT受体的亲和力)。这种选择的第二步如下述根据所述化合物的功能进行。本发明化合物的激动剂EC50值约为1μM或更小。本发明未考虑拮抗剂。
据信这两种方法是鉴定本发明有效化合物的最佳方法;然而,重要的是要注意到用该方法鉴定的某些化合物作为商业产品可能不如其它化合物那样合乎需要。必须考虑到正在讨论的化合物在其结构、物理特性,如溶解度、亲脂性和化学稳定性以及在眼部经代谢成为一种(或多种)非活性化合物的难易程度。这些参数的影响为本领域技术人员所熟知并可用本领域众所周知的方法测定。
除以上详述以外,某些5HT2激动剂如DOI、其异构体和相关化合物在全身用药时,已知会对人类造成中枢神经系统(CNS)副作用。在本发明中相信该化合物可以局部用药,以足够低的剂量降低并控制IOP,但不会造成某些化合物可能伴随产生的不必要CNS副作用。某些化合物特别合乎需要,因为它们的物理性质使其不能穿透CNS和产生副作用。此外,本发明的某些化合物在眼局部施用时可能导致局部过敏和不适,使其变得没有其它更舒适的化合物那么合意。这些可以用本领域熟知的方法毫不费力地确定。
实施例1
5HT2受体结合试验
为了测定5-羟色胺激活性化合物对5HT2受体的相对亲和力,如下述对Johnson等人的方法(神经药理学(Neuropharmacology),26,1803(1987))略作修改,测定它们与放射性配体[125I]DOI(一种激动剂)竞争结合脑5HT2受体的能力。将大鼠尸解物或人大脑皮质匀浆物的等份试样(400μl)分散在50mM的TrisHCl缓冲液(pH7.4)中,在没有或有美赛西平(methiothepin,5-HT1受体拮抗剂)(最终10μM)的情况下在0.5ml的总容积中与[125I]DOI(最终80pM)一起温育,以分别确定总结合和非特异性结合。将试验混合物于聚丙烯管中23℃温育1小时,通过在预先浸泡于应用冰冷却的缓冲液的0.3%聚乙烯亚胺中的whatman GF/B玻璃纤维滤膜上快速真空过滤终止试验。用待测化合物(不同浓度)替代美赛西平。结合于滤膜上的放射性在β计数器上用闪烁光谱测定法测定。用非线性的、迭代曲线拟合计算机程序(Bowen & Jerman,Trends Pharmacol.Sci.,16,413(1995))分析数据以测定化合物的亲和力参数。抑制最大[125I]DOI结合之50%所需的化合物浓度称为IC50或Ki值。如果IC50或Ki值≤50nM,认为化合物对5HT2受体具有高亲和力。
5HT2功能试验:磷酸肌醇(PI)转化试验
5-羟色胺激活性化合物对5HT2受体的相对激动剂活性可以在体外利用这些化合物的下述能力测定,即在[3H]myo-肌醇标记的A7r5大鼠血管平滑肌细胞中活化磷脂酶C,从而刺激[3H]肌醇磷酸酯生成的能力。将这些细胞于5%CO2和95%空气的一定湿度的气体环境中在培养皿上培养,每半周加一次Dulbecco改良型Eagle培养基(DMEM),其中含4.5g/l葡萄糖,并添加有2mM谷氨酰胺、10μg/ml庆大霉素和10%胎牛血清。为了进行磷酸肌醇(PI)转化试验,将A7r5细胞按前述在24孔培养板中培养(Griffin等,j.Pharmacol.Expt.Ther,286,411(1998))。融合细胞与0.5ml无血清培养基中1.5μCi[3H]-myo-肌醇(18.3Ci/mmol)接触24-30小时。然后细胞用含10mMLiCl的DMEM/F-12冲洗一次,再与检验试剂(或溶剂作为对照)在1.0ml的相同培养基中37℃温育1小时,然后吸出培养基并加入1ml冷的0.1M甲酸以终止反应。如前述(Griffin等,J.Pharmacol.Expt.Ther,286,411(1998))在AG-1-X8柱上层析分离[3H]-肌醇磷酸酯([3H]-IPs),依次用H2O和50mM甲酸铵洗脱,接着用含0.1M甲酸的1.2M甲酸铵洗脱[3H]-Ips总级分。收集洗脱物(4ml),与15ml闪烁液混合,在β计数器上用闪烁计数法测定总[3H]-Ips。浓度应答数据用Origin Scientific Graphics软件(Microcal Software,Northampton,MA)的S形曲线拟合函数分析以判定激动剂的潜能(EC50值)和功效(Emax)。5-羟色胺(5HT)用作阳性对照(标准)激动剂化合物,待检化合物的功效与5HT的功效(设置为100%)相比较。激发[3H]-Ips产生最大应答之50%所需化合物浓度称为EC50值。如果化合物在此功能试验中的EC50值≤1μM,可认为是强效激动剂;如果其功效大于5HT功效的80%可视为全效激动剂。
上述步骤用于产生表1所示数据。
表1.代表性化合物的5HT2受体结合和功能数据
化合物 | IC50,nM(SEM) | EC50,nM(SEM) | 功效(Emax,%) |
(R)-DOI | 0.5±0.2 | 277±35 | 82 |
α-甲基-5-羟色胺 | 3.5±0.9 | 189±26 | 104 |
5-甲氧基-α-甲基色胺 | 2.5±0.9 | 286±39 | 107 |
5-羟色胺 | 0.8±0.2 | 338±27 | 100 |
意识清醒的弥猴的激光的(高眼压)眼的急性IOP应答
用0.1%丙对卡因(proparacaine)轻度角膜麻醉后,用Alcon呼吸器量测定器(pneumatonometer)测定眼压(IOP)。每次测量后用生理盐水冲洗眼睛。测定基线IOP后,9只弥猴仅右眼注入30μL等分的待检化合物,另6只猴子右眼注入溶剂。接着在第1、3、6小时进行IOP测定。
表2提供了每一种化合物局部用药后的IOP应答特征。
表2.代表性化合物的IOP应答
实施例 | 剂量,μg | IOP基线(mmHg) | IOP降低百分比±SEM用药后小时数 | ||
1 | 3 | 6 | |||
(R)-DOI | 100 | 31.9 | 11.0±4.98 | 25.3±2.97 | 34.4±4.98 |
α-甲基-5-羟色胺 | 250 | 41.8 | 14.2±4.39 | 25.8±5.16 | 30.8±7.72 |
5-甲氧基-α-甲基色胺 | 300 | 38.1 | 21.6±5.05 | 35.2±6.12 | 33.4±5.39 |
5-羟色胺 | 250 | 33.5 | 13.3±5.31 | 18.0±5.12 | 2.0±7.39 |
按照本发明,根据有经验的临床医师的判断,以下眼部局部用药每天施用1-4次是有效的。
实施例2
成分 | 量(重量百分比) |
5HT2化合物 | 0.01-2% |
羟丙基甲基纤维素 | 0.5% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠盐(乙二胺四乙酸二钠) | 0.01% |
多乙氧基醚(Polysorbate 80) | 0.05% |
Benzalkonium chloride | 0.01% |
氢氧化钠/盐酸 | 用于调节pH至7.3-7.4 |
纯水 | 足量至100% |
实施例3
成分 | 量(重量百分比) |
5HT2化合物 | 0.01-2% |
羟丙基甲基纤维素 | 0.5% |
乳浮EL | 0.1% |
氨基丁三醇USP,AR | 0.64% |
甘露醇,USP | 3.0% |
硼酸,USP | 0.3% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠盐(乙二胺四乙酸二钠) | 0.01% |
多乙氧基醚 | 0.05% |
Benzalkonium chloride | 0.01% |
氢氧化钠/盐酸 | 用于调节pH至7.3-7.4 |
纯水 | 足量至100% |
实施例4
成分 | 量(重量百分比) |
5HT2化合物 | 0.01-2% |
甲基纤维素 | 4.0% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠盐(乙二胺四乙酸二钠) | 0.01% |
多乙氧基醚 | 0.05% |
Benzalkonium chloride | 0.01% |
氢氧化钠/盐酸 | 用于调节pH至7.3-7.4 |
纯水 | 足量至100% |
实施例5
成分 | 量(重量百分比) |
5HT2化合物 | 0.01-2% |
羟丙基-β-环糊精 | 4.0% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠盐(乙二胺四乙酸二钠) | 0.01% |
多乙氧基醚 | 0.05% |
Benzalkonium chloride | 0.01% |
氢氧化钠/盐酸 | 用于调节pH至7.3-7.4 |
纯水 | 足量至100% |
实施例6
成分 | 量(重量百分比) |
5HT2化合物 | 0.01-2% |
黄原胶 | 0.5-6.0% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠盐(乙二胺四乙酸二钠) | 0.01% |
多乙氧基醚 | 0.05% |
Benzalkonium chloride | 0.01% |
氢氧化钠/盐酸 | 用于调节pH至7.3-7.4 |
纯水 | 足量至100% |
实施例7
实施例8
成分 | 量(重量百分比) |
5HT2化合物 | 0.01-2% |
瓜耳树胶 | 0.4-6.0% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠盐(乙二胺四乙酸二钠) | 0.01% |
多乙氧基醚 | 0.05% |
Benzalkonium chloride | 0.01% |
氢氧化钠/盐酸 | 用于调节pH至7.3-7.4 |
纯水 | 足量至100% |
成分 | 量(重量百分比) |
5HT2化合物 | 0.01-2% |
四丁酚醛(Tyloxapol) | 0.2-4.0% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠盐(乙二胺四乙酸二钠) | 0.01% |
多乙氧基醚 | 0.05% |
Benzalkonium chloride | 0.01% |
氢氧化钠/盐酸 | 用于调节pH至7.3-7.4 |
纯水 | 足量至100% |
实施例9
成分 | 量(重量百分比) |
5HT2化合物 | 0.01-2% |
白凡士林和矿物油和羊毛脂 | 软膏稠度 |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠盐(乙二胺四乙酸二钠) | 0.01% |
多乙氧基醚 | 0.05% |
Benzalkonium chloride | 0.01% |
氢氧化钠/盐酸 | 用于调节pH至7.3-7.4 |
实施例10
成分 | 量(重量百分比) |
5HT2化合物 | 0.01-2% |
布莫尼啶 | 0.2% |
羟丙基甲基纤维素 | 0.5% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠盐(乙二胺四乙酸二钠) | 0.01% |
多乙氧基醚 | 0.05% |
Benzalkonium chloride | 0.01% |
氢氧化钠/盐酸 | 用于调节pH至7.3-7.4 |
纯水 | 足量至100% |
Claims (14)
1.一种治疗青光眼的方法,包括向需要该治疗的人施用一种组合物,该组合物含有药用有效量的具有5HT2受体激动剂活性的化合物。
2.权利要求1的方法,其中所述5HT2受体激动剂的浓度为占总重量的0.01%-5%。
3.权利要求2的方法,其中所述浓度为占总重量的0.25%-2%。
4.权利要求1的方法,其中所述5HT2受体激动剂为(R)-DOI、α-甲基-5-羟色胺、5-甲氧基-α-甲基色胺。
5.权利要求1的方法,其中所述组合物还包括选自β-阻滞剂、前列腺素、碳酸酐酶抑制剂、α2激动剂和缩瞳剂的另一种化合物。
6.权利要求5的方法,其中所述化合物为一种α2激动剂。
7.权利要求6的方法,其中所述α2激动剂选自阿普尼啶或布莫尼啶。
8.一种治疗青光眼的组合物,其包含药用有效量的具有5HT2受体激动剂活性的化合物。
9.权利要求8的组合物,其中所述5HT2受体激动剂的浓度为占总重量的0.01%-5%。
10.权利要求9的组合物,其中所述浓度为占总重量的0.25%-2%。
11.权利要求8的组合物,其中所述5HT2受体激动剂为(R)-DOI、α-甲基-5-羟色胺、5-甲氧基-α-甲基色胺。
12.权利要求8的组合物,其中所述组合物还包括选自β-阻滞剂、前列腺素、碳酸酐酶抑制剂、α2激动剂和缩瞳剂的另一种化合物。
13.权利要求12的组合物,其中所述化合物为一种α2激动剂。
14.权利要求13的组合物,其中所述α2激动剂选自阿普尼啶或布莫尼啶。
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WO1998018458A1 (en) * | 1996-10-31 | 1998-05-07 | Alcon Laboratories, Inc. | Opthalmological compositions containing serotonin 5-ht1a receptor agonist and their use in the treatment of glaucoma |
WO1998030546A1 (en) | 1997-01-08 | 1998-07-16 | F. Hoffmann-La Roche Ag | TRICYCLIC BENZO[e]ISOINDOLES AND BENZO[h]ISOQUINOLINES |
JP3560986B2 (ja) | 1997-01-13 | 2004-09-02 | 山之内製薬株式会社 | 5―ht2c受容体作用薬及びアミノアルキルインダゾール誘導体 |
GB9700899D0 (en) | 1997-01-17 | 1997-03-05 | Smithkline Beecham Plc | Novel treatment |
ES2208812T3 (es) | 1997-02-25 | 2004-06-16 | Akzo Nobel N.V. | Derivados de azetidina y de pirrolidina. |
AU727654B2 (en) | 1997-06-13 | 2000-12-21 | Yamanouchi Pharmaceutical Co., Ltd. | Tricyclic pyrazole derivative |
GB9718833D0 (en) | 1997-09-04 | 1997-11-12 | Merck Sharp & Dohme | Therapeutic agents |
-
1999
- 1999-09-03 JP JP2000573722A patent/JP2002526443A/ja active Pending
- 1999-09-03 WO PCT/US1999/019888 patent/WO2000016761A2/en not_active Application Discontinuation
- 1999-09-03 CN CNB99810891XA patent/CN1269484C/zh not_active Expired - Fee Related
- 1999-09-03 KR KR1020017003191A patent/KR20010073153A/ko not_active Application Discontinuation
- 1999-09-03 ES ES99948085T patent/ES2252978T3/es not_active Expired - Lifetime
- 1999-09-03 DK DK99948085T patent/DK1112106T3/da active
- 1999-09-03 US US09/787,332 patent/US6664286B1/en not_active Expired - Lifetime
- 1999-09-03 TR TR2001/00754T patent/TR200100754T2/xx unknown
- 1999-09-03 AU AU61326/99A patent/AU755119B2/en not_active Ceased
- 1999-09-03 BR BR9913800-0A patent/BR9913800A/pt not_active Application Discontinuation
- 1999-09-03 DE DE69928542T patent/DE69928542T2/de not_active Expired - Fee Related
- 1999-09-03 CA CA002344150A patent/CA2344150A1/en not_active Abandoned
- 1999-09-03 EP EP99948085A patent/EP1112106B1/en not_active Expired - Lifetime
- 1999-09-03 AT AT99948085T patent/ATE310566T1/de not_active IP Right Cessation
- 1999-09-14 AR ARP990104608A patent/AR020442A1/es unknown
- 1999-09-17 TW TW088116092A patent/TWI229602B/zh not_active IP Right Cessation
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2001
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- 2001-12-15 HK HK01108810A patent/HK1038516A1/xx not_active IP Right Cessation
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2003
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Also Published As
Publication number | Publication date |
---|---|
US20030203912A1 (en) | 2003-10-30 |
JP2002526443A (ja) | 2002-08-20 |
EP1112106B1 (en) | 2005-11-23 |
CN1269484C (zh) | 2006-08-16 |
BR9913800A (pt) | 2001-05-29 |
AR020442A1 (es) | 2002-05-15 |
TR200100754T2 (tr) | 2001-10-22 |
WO2000016761A2 (en) | 2000-03-30 |
AU6132699A (en) | 2000-04-10 |
WO2000016761A3 (en) | 2000-05-25 |
EP1112106A2 (en) | 2001-07-04 |
DK1112106T3 (da) | 2005-12-12 |
CA2344150A1 (en) | 2000-03-30 |
AU755119B2 (en) | 2002-12-05 |
KR20010073153A (ko) | 2001-07-31 |
DE69928542T2 (de) | 2006-03-30 |
ZA200102157B (en) | 2003-03-05 |
HK1038516A1 (en) | 2002-03-22 |
DE69928542D1 (de) | 2005-12-29 |
ATE310566T1 (de) | 2005-12-15 |
US6664286B1 (en) | 2003-12-16 |
TWI229602B (en) | 2005-03-21 |
ES2252978T3 (es) | 2006-05-16 |
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